The mammalian target of rapamycin pathway as a therapeutic target in multiple myeloma.

The mammalian target of rapamycin (mTOR) is centrally located, linking proximal oncogenic cascades to critical downstream pathways that drive tumor growth. mTOR regulates such diverse functions as protein translation, proliferation, viability, autophagy, metabolism homeostasis, monitoring of energy reserves, and induction of angiogenesis. Given its fundamental role in tumorigenesis, it is not surprising that a huge effort is being made to develop mTOR inhibitors. The existence of feedback pathways that become activated subsequent to mTOR inhibition has complicated these efforts. However, the fact that mTOR exists in two separate complexes, TORC1 and TORC2, and rapalogs primarily inhibit only TORC1 and TORC2 is actually a key activator of AKT, has injected new energy into the quest to find inhibitors that can inhibit both complexes. In myeloma models, preclinical studies confirm the activity of rapalogs as well as newer TORC1/TORC2 inhibitors, and early phase clinical trials have begun. In addition, the recent finding of up-regulated myeloma cell expression of DEPTOR, an mTOR binding protein that restricts mTOR activity, suggests an additional future therapeutic target specific to the myeloma tumor model.